This proposal aims to experimentally and computationally study how the brain learns and generates complex sequences of actions. Since behaviors emerge from the dynamic interplay of many brain areas, computational models that permit the study of distributed circuits are important. Such models can unify results across multiple experiments and brain areas to provide insights into neural circuit computations and, importantly, to generate experimental predictions. To provide experimental constraints for such models, a motor learning paradigm is needed in which subjects can be reliably trained, their behavior quantified, and neural activity in relevant circuits measured and manipulated. The rodent motor sequence task developed and studied in the Olveczky lab conforms to these criteria, and hence can serve to constrain, refine, and arbitrate between different computational models, and serve as an experimental test-bed for their predictions. The computational effort, led by the Escola lab, will start with an exploration of circuit models consistent with available data. Further analysis of these models will generate competing predictions and ideas for experiments that arbitrate between them. The goal of this collaboration is to arrive at a circuit-level description of how complex motor sequences are learned and produced in the form of a biologically plausible computational model that can be refined and updated as new experimental results arrive. Recordings from neurons in the striatum (a major motor system structure) reveal the existence of sequence cells-- neurons that are sparsely active and precisely time-locked to the motor output. Additionally, the Olveczky lab showed that motor cortex is essential for learning the task, but can be lesioned without impairing task execution. These results raise important questions: 1) Is sequence cell activity in the striatum driving the learned motor sequences, and if so, is this dynamics generated independently of motor cortex? 2) How do other motor-related circuits contribute to striatal dynamics and ultimately behavior? 3) How do the circuits controlling complex motor sequences learn, i.e. where are the sites of plasticity within these circuits and what learning rules govern their adaptive reorganization? A computational modeling framework, constrained by experimental results, which rigorously and quantitatively addresses these questions, will advance our understanding of how the motor system produces learned motor sequences. This understanding will provide a new framework within which to consider the pathogenesis of movement <ii><or<iAro:; ><11r.h Prkin><nn'>< nrl H11ntinntnn'>< rli><A' D RELEVANCE (See Instructions): Movement disorders such as Parkinson's and Huntington's constitute a major disease burden. Contributing to the difficulty in understanding how the brain controls movement and thus may be disordered in disease is the fact that many brain areas interact to generate movements. In this proposal, animal experiments will be coupled with computer modeling of these parts of the brain to facilitate our ability understand their interactions and role in the develooment of disease. n